Sjogren's syndrome is a systemic autoimmune disease that most commonly targets the exocrine glands and is characterized by persistent dry eyes and mouth as well as extra-glandular involvement including blood vessel, skin, kidney, joints, and lung disease along with an increased risk of lymphoma. Salivary gland lymphocytic infiltrates are a pathological finding in the disease. The serum of these patients commonly contains autoantibodies to Ro (SS-A) and La (SS-B). Other specificities are present, including those towards muscarinic receptors. There are strong data supporting significant autoreactive B cell expansion, hyperreactivity and antibody formation in exocrine glands of Sjogren's patient, including the presence of anti-Ro and -La specific B cells. The evidence is strong that B cells infiltrating the salivary glands of Sjogren's patients make autoantibodies that are in part responsible for the exocrine glandular dysfunction. This proposal will test the hypothesis that this is the case, and will address the pathogenic mechanisms underlying this dysfunction. We will utilize an innovative, humanized model of Sjogren's in which human salivary tissue is transplanted into NOD SCID mice. So transplanted mice are already available (see Preliminary Data). In addition, we will use an innovative method of producing recombinant monoclonal antibodies to study the autoantibody repertoire produced in the salivary gland of humans with Sjogren's. Already we have harvested B cells from minor salivary glands and begun the process of producing recombinant monoclonals antibodies (see Preliminary Data). First, we will produce recombinant monoclonal antibodies from B cells infiltrating the salivary glands of humans with Sjogren's syndrome. Then, these monoclonal antibodies will be tested for pathogenicity, that is, the ability to reduce salivary flow in either normal mice, or the xenotransplanted Sjogren's mouse model. We will study the binding specificity of pathogenic autoantibodies. Furthermore, the pathogenic mechanisms by which these antibodies cause the characteristic salivary gland dysfunction will be elucidated.